Intermediates useful in the synthesis of vitamin a

ABSTRACT

Are useful intermediates for producing vitamin A into which they may be converted by saponification, desulphonation, and reduction.   And a sulphone of the formula:   In which R is aryl and Q is hydrogen or a hydrocarbon radical, which are made by reacting, preferably at low temperature, a halide of the formula:   Sulphones of the formula:

United States Patent Julia [111 3,876,673 [4 1 *Apr. 8,1975

[ INTERMEDIATES USEFUL IN THE SYNTHESIS OF VITAMIN A [75] Inventor: Marc Julia, Paris, France [73] Assignee: Rhone-Poulenc S.A., Paris, France 1 Notice: The portion of the term of this patent subsequent to Dec. 25, 1990, has been disclaimed.

[22] Filed: Dec. 29, 1972 21 Appl. No; 319,673

Related US. Application Data- [62] Division of Ser. No. 169,] l4. Aug. 4, l97l, Pat. No.

[30] Foreign Application Priority Data OTHER PUBLlCATlONS Corey et al., .I.A.C.S., 87, l345l353, 1965.

Primary E.\'aminer-Lewis Gotts Assistant Examiner-Ethel G. Love Attorney, Agent, or Firm-Stevens, Davis, Miller & Mosher [57] ABSTRACT Sulphones of the formula:

Ho :1. i io Mo c 0x 8 00 a in which R is ai'yl and Q is hydrogen or a hydrocarbon radical. which are made by reacting, preferably at low temperature, a halide of the formula:

Me Me Me 0112 O\E/.OH\QH/ oa one! in,

and a sulphone of the formula:

R 80 CH are useful intermediates for producing vitamin A into which they may be converted by saponification, desulphonation, and reduction.

1 :Claim, No Drawings l 2 INTERMEDIATES USEFUL IN THE SYNTHESIS OF out in the presence of an acceptor, e.g. an alkali metal VITAMIN A butylate, for the hydrogen halide liberated. Usually, a

. solution of the halide of formula II is slowly added to This is a division, of application Ser.:'No.' 169,114, the mixture of the other constituents of the reaction filed Aug. 4, 1971, now U.S. Pat; No. 3,748,347. mixture. After the reaction and after the usual prelimi- The present invention relates to intermediates useful nary purification treatments, the sulphone of formula in the synthesis of vitamin A. lmay be isolated in the pure state, for example by chro- The present invention provides, as new compounds matography.

useful as intermediates in the synthesis of vitamin A, The halide of formula I] may be obtained by halogethe sulphones of the formula: nation of vinyl-B-ionol with a phosphorus trihalide.

KO/i. CH 2 H 1 00 a $4 a (m c/ N/ \H in which R represents an aryl radical and Q represents The sulphones of formula III which are new coma hydrogen atom or a monovalent hydrocarbon radical. pounds, may be obtained by reaction of an alkali metal R can in particular represent naphthyl, phenyl or alkylsulphinate of formula RSO M, in which M represents phenyl, in which the alkyl is preferably of l to 4 carbon an alkali metal, with a 'y-halogenosenecioate of a monatoms, such as p-toluyl. Q can be, for exampple, an alovalent hydrocarbon radical, which is in turn obtainkyl, cycloalkyl, aryl or aralkyl radical, but is preferably able by halogenation of the corresponding senecioate analkyl radical of l to 4 carbon atoms, such as methyl with an N-halogenosuccinimide, for example by bromior ethyl. nation withN-bromosuccinimide.

The sulphones of formula I are obtained in accor- Desulphonation of the sulphones of formula I in dance with a feature of the invention by reaction of a which Q represents hydrogen, yields the acid of forhalide of the formula: mula O 0 II 3 2 g a on CH Me lh\ /Ho I39 3 O OH 0008 C cn ca ox l 0H2 He in which X represents a chlorine, bromine or iodine As is already known,reduction ofthe terminal carboxyl atom, with a sulphone of the formula: radical of this acid to give a hydroxymethyl radical CH OH yields vitamin A. When Q in the sulphone of formula I is initially a hydrocarbon radical, the latter is R80 0 first replaced by hydrogen by saponification.

K m The Example which follows illustrates the invention.

EXAMPLE Potassium t-butylate (6.9 g.) in tetrahydrofuran 40 cc.), followed by the sulphone (16.5 g. 0.06 mol) of in which R and Q have the meanings given above. It IS formula.

to be understood that the formulae 1 and Ill do not necessarily represent sterically pure products, but can rep- P11 resent mixtures of cis and trans isomers. c CH COOEt The reaction of the halide of formula II with the sulphone of formula III is preferably carried out at between -40 and 0C., and usually at between -35 and are introduced, at 20C., into a three-neck flask of 250 25C. It is advantageous to carry out the reaction in cc. capacity, equipped with a mechanical stirrer. A hothe presence of a solvent, especially an ether. such as mogeneous blood-red solution (carbanion formation) tetrahydrofuran or dioxane, or another aprotic polar is thus obtained.

solvent, such as dimethylformamide, dimethylsulph- The whole is cooled tor-30C. and a solution of 21.7 oxide, hexamethylphosphorylamide 1 .or. N- g. of a product containing percent of the bromide of methylpyrrolidone. Generally, the process is'carricdformula:

Me Me in anhydrous tetrahydrofuran cc.) is added droprated in vacuo and the reaction mixture is taken up in water. The neutral fraction and the acid fraction are separated in the usual manner. The neutral fraction (36.9 g.) is a red oil containing 37 percent of products of formula:

Me Me e on on cn lba 2 are introduced into a flask equipped with a stirrer. The whole is cooled to -35C. with stirring and a mixture of anhydrous diethyl ether (1 cc.) and phosphorus tribromide (0.9 g.) is added dropwise with stirring. When the addition is complete, stirring is continued for a further minutes at -C., and the temperature is then allowed to rise to 0C., again and is kept at 0C. for 1 hour, with continued stirring.

cold water; the combined ether layeyrs are dried over magnesium sulphate. After evaporation of the ether at 0C., a crude bromide (2.17 g.), containaing percent of the bromide of formula IV, is obtained. The yield of the bromide of formula IV is thus 60 percent based on the vinyl-B-ionol introduced. This bromide is not stable in the pure state and at ambient temperature. lt-is desirable therefore to store it in solution in diethyl ether under nitrogen at a temperature below 0C.

b. Ethyl y-(phenylsulphonyl)senecioate was prepared by reaction of sodium phenylsulphinate, PhSO Na, with ethyl 'y-bromosenecioate.

Sodium phenylsulphinate (16.4 g., 0.1 mol) is dissolved in anhydrous methanol (35 cc.) in a three-neck flask equipped with a mechanical stirrer. Ethyly-bromosenecioate (20.7 g., 0.1 mol) is added dropwise at 20C. A yellow precipitate appears. After completion of the addition, the mixture is stirred for a further 10 minutes. The methanol is distilled off and progressively replaced by an equal volume of water. After cooling, the aqueous phase is extracted with diethyl ether and the organic layers are combined. The whole is washed with water and then dried over magnesium sulphate. After evaporation of the solvent, ethyl 'y-(phenylsulphonyl)senecioate (24.75 g.) (92% yield) is obtained as a practically colourless liquid.

Ethyl y-bromosenecioate (mixture of cis and trans isomers) was prepared by bromination of ethyl senecioate with N-bromosuccinimide, in a yield of 67 percent based on the N-bromosuccinimide, by the method described by l. AHMAD et a1. .1. Chem. Soc. 1958 C to 187.

The final sulphone-ester of formula I, in which R represents a phenyl radical and Q represents an ethyl radical, can be used as follows:

10 g. of this sulphone-ester (0.021 mole) 20 cc. of 96 percent ethanol and 3.5 g. of potassium hydroxyde (0.064 mole) are kept at boiling temperature under reflux for two hours. After cooling the acid fraction (6.4 g.) is separated in the usual manner. By recrystallization of this acid fraction in petrol ether, 73 mg. of vitamine A acid of formula The ether phase is decanted, the residue is washed with diethyl ether, and the ether layers are combined and washed with an ice-cold solution of sodium bicarbonate. The aqueouslayer is-extracted with diethyl ether and the ether layer is rapidly washed with iceare obtained (mp. b l77-179C) (12% yield).

1 claim:

" l.- Process for the preparation of vitamin A acid which comprises desulphonating a sulphone of the formula: g

M M M e e Ii 1e le CH c CH C CO Q 2 2 (SH 5 \CH/ \CH/ \CH/ \CH/ I CH c 502R CH2 Me in which R represents an aryl radical and Q represents by saponification when Q is alkyl of l to 4 carbon hydrogen or alkyl of l to 4 carbon atoms, by treatment atoms. with alkali, the said desulphonation being accompanied. 

1. PROCESS FOR THE PREPARATION OF VITAMIN A ACID WHICH COMPRISES DESULPHONATING A SULPHONE OF THE FORMULA: 1-(Q-OOC-CH=C(-ME)-CH(-SO2-R)-CH2-CH=C(-ME)-CH=CH-), 2,6,6-TRI(ME-)CYCLOHEX-1-ENE IN WHICH R REPRESENTS AN ARYL RADICAL AND Q REPRESENTS HYDROGEN OR ALKYL OF 1 TO 4 CARBON ATOMS, BY TREATMENT WITH ALKALI, THE SAID DESULPHONATION BEING ACCOMPANIED BY SAPONIFICATION WHEN Q IS ALKYL OF 1 TO 4 CARBON ATOMS. 